Congenital malformations, mental retardation and genetic disorders together constitute a major source of morbidity and mortality in childhood and beyond. Some 25-30% of all admissions to children's hospitals in the western world are for these categories of disease. The serious personal, family and societal health burden and costs require no emphasis. The most common major congenital defects are neural tube defects (NTD's) and trisomies. For NTD's maternal serum alfa-fetoprotein (MSAFP) screening has been available for 10 years and second trimester screening by MSAFP for both NTD's (high values) and trisomies (low values) now serves as a non-specific signal of pregnancies at risk. We have developed a highly sensitive and specific monoclonal radioimmunometric assay (M-IRMA) for measurement of MSAFP that is very accurate at low serum levels (0.5-10 ng/ml). A preliminary study has been performed in women undergoing chorionic villus biopsy (CVS) to determine whether it would be possible in the first trimester to recognize a group of women who unknowing had an increased risk of carrying a fetus with a serious chromosome defect. Overall, we demonstrated that 30% of all chromosome defects were reflected by MSAFP values less than 0.6 MOM which is remarkedly similar to the observations of others in the second trimester. More importantly, during the previous grant period, we developed new monoclonal and antipeptide monoclonal IRMAs for hCG and its free subunits (beta hCG and alpha CG) to study trophoblastic differentiation since it seemed possible that the trophoblast may be abnormal under these conditions. Indeed, using our M-RMAs in combination, we found in a high risk population that 80% (14/18) of all trisomies had MSAFP and the beta HCG ratio of less than 0.6 MOM in the first trimester and thus identified such pregnancies at risk (P less than 10-8). We wish to consolidate and extend these gains and perform a large scale prospective first trimester clinical trial to screen non-selected pregnancies for fetal chromosome abnormalities. Finally, we will explore the mechanism(s) of hCG free beta HCG and alpha HCG subunit production and secretion by trophoblastic tissue and examine the value of these IRMAs in the diagnosis and follow- up of patients with trophoblastic disease. Thus, we have provided new clinical tools, the comparative value of which will be determined in an established program and are optimistic that new data of biologic and clinical significance will be forthcoming and the evolution of a better standard of patient care may be possible.